"The U.S. Food and Drug Administration today approved Aptiom (eslicarbazepine acetate) as an add-on medication to treat seizures associated with epilepsy.
Epilepsy is a brain disorder caused by abnormal or excessive activity in the brain"...
Mechanism Of Action
The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state. The relevance of these models to human epilepsy, however, is not known.
One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).
Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity
Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 μM of glycine) in cultured hippocampal neurons exceeded 100 μM.
In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced. Significantly reduced concentrations of folate are associated with teratogenesis [see Use in Specific Populations]. Folate concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were partially returned to normal when supplemented with folinic acid.
In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongation of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite ( < 0.6% of lamotrigine dose) have been found in human urine [see Pharmacokinetics]. However, it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease, patients taking concomitant medications that inhibit glucuronidation).
In comparison with immediate-release lamotrigine, the plasma lamotrigine levels following administration of LAMICTAL XR are not associated with any significant changes in trough plasma concentrations, and are characterized by lower peaks, longer time to peaks, and lower peak-to-trough fluctuation, as described in detail below.
Lamotrigine is absorbed after oral administration with negligible first-pass metabolism. The bioavailability of lamotrigine is not affected by food.
In an open-label, crossover study of 44 subjects with epilepsy receiving concomitant AEDs, the steady-state pharmacokinetics of lamotrigine were compared following administration of equivalent total doses of LAMICTAL XR given once daily with those of lamotrigine immediate-release given twice daily. In this study, the median time to peak concentration (Tmax) following administration of LAMICTAL XR was 4 to 6 hours in subjects taking carbamazepine, phenytoin, phenobarbital, or primidone; 9 to 11 hours in subjects taking valproate; and 6 to 10 hours in subjects taking AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate. In comparison, the median Tmax following administration of immediate-release lamotrigine was between 1 and 1.5 hours.
The steady-state trough concentrations for extended-release lamotrigine were similar to or higher than those of immediate-release lamotrigine depending on concomitant AED (Table 6). A mean reduction in the lamotrigine Cmax by 11% to 29% was observed for LAMICTAL XR compared with immediate-release lamotrigine, resulting in a decrease in the peak-to-trough fluctuation in serum lamotrigine concentrations. However, in some subjects receiving enzyme-inducing AEDs, a reduction in Cmax of 44% to 77% was observed. The degree of fluctuation was reduced by 17% in subjects taking enzyme-inducing AEDs; 34% in subjects taking valproate; and 37% in subjects taking AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate. LAMICTAL XR and immediate-release lamotrigine regimens were similar with respect to area under the curve (AUC, a measure of the extent of bioavailability) for subjects receiving AEDs other than those known to induce the metabolism of lamotrigine. The relative bioavailability of extended-release lamotrigine was approximately 21% lower than immediate-release lamotrigine in subjects receiving enzyme-inducing AEDs. However, a reduction in exposure of up to 70% was observed in some subjects in this group when they switched to LAMICTAL XR. Therefore, doses may need to be adjusted in some patients based on therapeutic response.
Table 6: Steady-State Bioavailability of LAMICTAL XR
Relative to Immediate-Release Lamotrigine at Equivalent Daily Doses (Ratio of
Extended-Release to Immediate-Release 90% CI)
|Concomitant Antiepileptic Drug||AUC(0-24ss)||Cmax||Cmin|
|Enzyme-inducing antiepileptic drugsa||0.79
|Antiepileptic drugs other than enzyme-inducing antiepileptic drugsa or valproate||1.00
|aEnzyme-inducing antiepileptic drugs include carbamazepine, phenytoin, phenobarbital, and primidone.|
In healthy volunteers not receiving any other medications and given LAMICTAL XR once daily, the systemic exposure to lamotrigine increased in direct proportion to the dose administered over the range of 50 to 200 mg. At doses between 25 and 50 mg, the increase was less than dose proportional, with a 2-fold increase in dose resulting in an approximately 1.6-fold increase in systemic exposure.
Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.
Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein-binding sites.
Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).
The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated.
Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a 37% increase in CL/F at steady state compared with values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see DRUG INTERACTIONS].
The elimination half-life and apparent clearance of lamotrigine following oral administration of immediate-release lamotrigine to adult subjects with epilepsy and healthy volunteers is summarized in Table 7. Half-life and apparent oral clearance vary depending on concomitant AEDs.
Since the half-life of lamotrigine following administration of single doses of immediate-release lamotrigine is comparable with that observed following administration of LAMICTAL XR, similar changes in the half-life of lamotrigine would be expected for LAMICTAL XR.
Table 7: Mean Pharmacokinetic Parametersa of
Immediate-Release Lamotrigine in Healthy Volunteers and Adult Subjects With
|Adult Study Population||Number of Subjects||t½: Elimination Half-life (h)||CL/F: Apparent Plasma Clearance (mL/min/kg)|
|Healthy volunteers taking no other medications:|
|Healthy volunteers taking valproate:|
|Subjects with epilepsy taking valproate only:|
|Subjects with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidoneb plus valproate:|
|Subjects with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone:b|
|aThe majority of parameter means determined in each study
had coefficients of variation between 20% and 40% for half-life and CL/F and
between 30% and 70% for Tmax. The overall mean values were calculated from
individual study means that were weighted based on the number of
volunteers/subjects in each study. The numbers in parentheses below each
parameter mean represent the range of individual volunteer/subject values
bCarbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs, such as rifampin and protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir, that induce lamotrigine glucuronidation have also been shown to increase the apparent clearance of lamotrigine [see DRUG INTERACTIONS].
The net effects of drug interactions with lamotrigine, based on drug interaction studies using immediate-release lamotrigine, are summarized in Tables 5 and 8, followed by details of the drug interaction studies below.
Table 8: Summary of Drug
Interactions With Lamotrigine
|Drug||Drug Plasma Concentration With Adjunctive Lamotriginea||Lamotrigine Plasma Concentration With Adjunctive Drugsb|
|Oral contraceptives (e.g., ethinylestradiol/levonorgestrel)c||↔d||↓|
|10-Monohydroxy oxcarbazepine metaboliteh||↔|
|Valproate + phenytoin and/or carbamazepine||Not assessed||↔|
|aFrom adjunctive clinical trials and volunteer
bNet effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and volunteer trials.
c The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials, although the effect may be similar to that seen with the ethinylestradiol/levonorgestrel combinations.
dModest decrease in levonorgestrel.
eSlight decrease, not expected to be clinically meaningful.
fCompared to historical controls.
gNot administered, but an active metabolite of carbamazepine.
hNot administered, but an active metabolite of oxcarbazepine.
iNot administered, but an active metabolite of risperidone.
j Slight increase, not expected to be clinically meaningful.
↔ = No significant effect.
? = Conflicting data.
Estrogen-Containing Oral Contraceptives
In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with mean decreases in AUC of 52% and in Cmax of 39%. In this study, trough serum lamotrigine concentrations gradually increased and were approximately 2-fold higher on average at the end of the week of the inactive hormone preparation compared with trough lamotrigine concentrations at the end of the active hormone cycle.
Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase) occurred during the week of inactive hormone preparation (pill-free week) for women not also taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation) [see DRUG INTERACTIONS]. The increase in lamotrigine plasma levels will be greater if the dose of LAMICTAL XR is increased in the few days before or during the pill-free week. Increases in lamotrigine plasma levels could result in dose-dependent adverse reactions.
In the same study, coadministration of lamotrigine (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There were mean decreases in the AUC and Cmax of the levonorgestrel component of 19% and 12%, respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.
The effects of doses of lamotrigine other than 300 mg/day have not been systematically evaluated in controlled clinical trials.
The clinical significance of the observed hormonal changes on ovulatory activity is unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded. Therefore, patients should be instructed to promptly report changes in their menstrual pattern (e.g., break-through bleeding).
Dosage adjustments may be necessary for women receiving estrogen-containing oral contraceptive preparations [see DOSAGE AND ADMINISTRATION].
Other Hormonal Contraceptives or Hormone Replacement Therapy
The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of LAMICTAL XR in the presence of progestogens alone will likely not be needed.
In 18 patients with bipolar disorder on a stable regimen of 100 to 400 mg/day of lamotrigine, the lamotrigine AUC and Cmax were reduced by approximately 10% in patients who received aripiprazole 10 to 30 mg/day for 7 days, followed by 30 mg/day for an additional 7 days. This reduction in lamotrigine exposure is not considered clinically meaningful.
In a study in healthy volunteers, daily doses of atazanavir/ritonavir (300 mg/100 mg) reduced the plasma AUC and Cmax of lamotrigine (single 100-mg dose) by an average of 32% and 6%, respectively, and shortened the elimination half-lives by 27%. In the presence of atazanavir/ritonavir (300 mg/100 mg), the metabolite-to-lamotrigine ratio was increased from 0.45 to 0.71 consistent with induction of glucuronidation. The pharmacokinetics of atazanavir/ritonavir were similar in the presence of concomitant lamotrigine to the historical data of the pharmacokinetics in the absence of lamotrigine.
The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy volunteers (n = 12) were not changed by coadministration of bupropion sustained-release formulation (150 mg twice daily) starting 11 days before lamotrigine.
Lamotrigine has no appreciable effect on steady-state carbamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine [see ADVERSE REACTIONS]. The mechanism of this interaction is unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels increased.
The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately 40%.
In a study of 30 subjects, coadministration of LAMICTAL XR with esomeprazole resulted in no significant change in lamotrigine levels and a small decrease in Tmax. The levels of gastric pH were not altered compared with pre-lamotrigine dosing.
In a trial in 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.
Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.
Based on a retrospective analysis of plasma levels in 34 subjects who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.
Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.
The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by coadministration of lamotrigine (100 mg/day) for 6 days.
The addition of lopinavir (400 mg twice daily)/ritonavir (100 mg twice daily) decreased the AUC, Cmax, and elimination half-life of lamotrigine by approximately 50% to 55.4% in 18 healthy subjects. The pharmacokinetics of lopinavir/ritonavir were similar with concomitant lamotrigine, compared to that in historical controls.
The AUC and Cmax of olanzapine were similar following the addition of olanzapine (15 mg once daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared with the AUC and Cmax in healthy male volunteers receiving olanzapine alone (n = 16).
In the same trial, the AUC and Cmax of lamotrigine were reduced on average by 24% and 20%, respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers compared with those receiving lamotrigine alone. This reduction in lamotrigine plasma concentrations is not expected to be clinically meaningful.
The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 13) compared with healthy male volunteers receiving oxcarbazepine alone (n = 13).
In the same trial, the AUC and Cmax of lamotrigine were similar following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers compared with those receiving lamotrigine alone. Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine compared with lamotrigine alone or oxcarbazepine alone.
The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by approximately 40%.
Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately 40%.
Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine and pregabalin.
In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance of a single 25-mg dose of lamotrigine by approximately 2-fold (AUC decreased by approximately 40%).
In a 14 healthy volunteers study, multiple oral doses of lamotrigine 400 mg daily had no clinically significant effect on the single-dose pharmacokinetics of risperidone 2 mg and its active metabolite 9-OH risperidone. Following the coadministration of risperidone 2 mg with lamotrigine, 12 of the 14 volunteers reported somnolence compared with 1 out of 20 when risperidone was given alone, and none when lamotrigine was administered alone.
Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.
When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the trough steady-state valproate plasma concentrations decreased by an average of 25% over a 3-week period, and then stabilized. However, adding lamotrigine to the existing therapy did not cause a change in valproate plasma concentrations in either adult or pediatric patients in controlled clinical trials.
The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers by slightly more than 2-fold. In 1 trial, maximal inhibition of lamotrigine clearance was reached at valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was further increased.
In a study in 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day for 35 days) had no significant effect on the pharmacokinetics of lamotrigine.
Known Inducers or Inhibitors of Glucuronidation
Drugs other than those listed above have not been systematically evaluated in combination with lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of LAMICTAL XR may require adjustment based on clinical response.
In vitro assessment of the inhibitory effect of lamotrigine at OCT2 demonstrate that lamotrigine, but not the N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant concentrations, with IC50 value of 53.8 μM [see DRUG INTERACTIONS].
Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, sertraline, or trazodone.
Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6.
Renal Impairment: Twelve volunteers with chronic renal failure (mean creatinine clearance: 13 mL/min, range: 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100-mg dose of immediate-release lamotrigine. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared with 26.2 hours in healthy volunteers. On average, approximately 20% (range: 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour session [see DOSAGE AND ADMINISTRATION].
Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose of immediate-release lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic impairment (Child-Pugh Classification system) and compared with 12 subjects without hepatic impairment. The subjects with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearances of lamotrigine in subjects with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared with 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in subjects with mild, moderate, severe without ascites, and severe with ascites hepatic impairment were 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy controls [see DOSAGE AND ADMINISTRATION].
Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of immediate-release lamotrigine were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance: 61 mL/min, range: 33 to 108 mL/min). The mean half-life of lamotrigine in these subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).
Gender: The clearance of lamotrigine is not affected by gender. However, during dose escalation of immediate-release lamotrigine in 1 clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough lamotrigine concentrations unadjusted for weight were 24% to 45% higher (0.3 to 1.7 mcg/mL) in females than in males.
Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians.
Pediatric Patients: Safety and effectiveness of LAMICTAL XR for use in patients younger than 13 years have not been established.
Adjunctive Therapy For Primary Generalized Tonic-Clonic Seizures
The effectiveness of LAMICTAL XR as adjunctive therapy in subjects with PGTC seizures was established in a 19-week, international, multicenter, double-blind, randomized, placebo-controlled trial in 143 patients aged 13 years and older (n = 70 on LAMICTAL XR, n = 73 on placebo). Patients with at least 3 PGTC seizures during an 8-week baseline phase were randomized to 19 weeks of treatment with LAMICTAL XR or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target doses ranging from 200 to 500 mg/day of LAMICTAL XR based on concomitant AEDs (target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine levels, and 500 mg for enzyme-inducing AEDs).
The primary efficacy endpoint was percent change from baseline in PGTC seizure frequency during the double-blind treatment phase. For the intent-to-treat population, the median percent reduction in PGTC seizure frequency was 75% in patients treated with LAMICTAL XR and 32% in patients treated with placebo, a difference that was statistically significant, defined as a 2-sided P value ≤ 0.05.
Figure 1 presents the percentage of patients (X-axis) with a percent reduction in PGTC seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in PGTC seizure frequency was consistently higher for the group treated with LAMICTAL XR compared with the placebo group. For example, 70% of patients randomized to LAMICTAL XR experienced a 50% or greater reduction in PGTC seizure frequency, compared with 32% of patients randomized to placebo. Patients with an increase in seizure frequency > 100% are represented on the Y-axis as equal to or greater than -100%.
Figure 1: Proportion of Patients by Responder Rate for
LAMICTAL XR and Placebo Group (Primary Generalized Tonic-Clonic Seizures Study)
Adjunctive Therapy For Partial-Onset Seizures
The effectiveness of immediate-release lamotrigine as adjunctive therapy was initially established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial-onset seizures.
The effectiveness of LAMICTAL XR as adjunctive therapy in partial-onset seizures, with or without secondary generalization, was established in a 19-week, multicenter, double-blind, placebo-controlled trial in 236 patients aged 13 years and older (approximately 93% of patients were aged 16 to 65 years). Approximately 36% were from the U.S. and approximately 64% were from other countries including Argentina, Brazil, Chile, Germany, India, Korea, Russian Federation, and Ukraine. Patients with at least 8 partial-onset seizures during an 8-week prospective baseline phase (or 4-week prospective baseline coupled with a 4-week historical baseline documented with seizure diary data) were randomized to treatment with LAMICTAL XR (n = 116) or placebo (n = 120) added to their current regimen of 1 or 2 AEDs. Approximately half of the patients were taking 2 concomitant AEDs at baseline. Target doses ranged from 200 to 500 mg/day of LAMICTAL XR based on concomitant AED (target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine, and 500 mg for enzyme-inducing AEDs). The median partial seizure frequency per week at baseline was 2.3 for LAMICTAL XR and 2.1 for placebo.
The primary endpoint was the median percent change from baseline in partial-onset seizure frequency during the entire double-blind treatment phase. The median percent reductions in weekly partial-onset seizures were 47% in patients treated with LAMICTAL XR and 25% on placebo, a difference that was statistically significant, defined as a 2-sided P value ≤ 0.05.
Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial-onset seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. The proportion of patients achieving any particular level of reduction in partial-onset seizure frequency was consistently higher for the group treated with LAMICTAL XR compared with the placebo group. For example, 44% of patients randomized to LAMICTAL XR experienced a 50% or greater reduction in partial-onset seizure frequency compared with 21% of patients randomized to placebo.
Figure 2: Proportion of Patients by Responder Rate for
LAMICTAL XR and Placebo Group (Partial-Onset Seizure Study)
Conversion To Monotherapy For Partial-Onset Seizures
The effectiveness of LAMICTAL XR as monotherapy for partial-onset seizures was established in a historical control trial in 223 adults with partial-onset seizures. The historical control methodology is described in a publication by French, et al. [see REFERENCES]. Briefly, in this study, patients were randomized to ultimately receive either LAMICTAL XR 300 or 250 mg once a day, and their responses were compared with those of a historical control group. The historical control consisted of a pooled analysis of the control groups from 8 studies of similar design, which utilized a subtherapeutic dose of an AED as a comparator. Statistical superiority to the historical control was considered to be demonstrated if the upper 95% confidence interval for the proportion of patients meeting escape criteria in patients receiving LAMICTAL XR remained below the lower 95% prediction interval of 65.3% derived from the historical control data.
In this study, patients aged 13 years and older experienced at least 4 partial-onset seizures during an 8-week baseline period with at least 1 seizure occurring during each of 2 consecutive 4-week periods while receiving valproate or a non–enzyme-inducing AED. LAMICTAL XR was added to either valproate or a non–enzyme-inducing AED over a 6-to 7-week period followed by the gradual withdrawal of the background AED. Patients were then continued on monotherapy with LAMICTAL XR for 12 weeks. The escape criteria were 1 or more of the following: (1) doubling of average monthly seizure count during any 28 consecutive days, (2) doubling of highest consecutive 2-day seizure frequency during the entire treatment phase, (3) emergence of a new seizure type compared with baseline (4) clinically significant prolongation of generalized tonic-clonic seizures or worsening of seizure considered by the investigator to require intervention. These criteria were similar to those in the 8 controlled trials from which the historical control group was constituted.
The upper 95% confidence limits of the proportion of subjects meeting escape criteria (40.2% at 300 mg/day and 44.5% at 250 mg/day) were below the threshold of 65.3% derived from the historical control data.
Although the study population was not fully comparable with the historical controlled population and the study was not fully blinded, numerous sensitivity analyses supported the primary results. Efficacy was further supported by the established effectiveness of the immediate-release formulation as monotherapy.
1. French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy. Epilepsia. 2010; 51(10):1936-1943.
Last reviewed on RxList: 4/14/2015
This monograph has been modified to include the generic and brand name in many instances.
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